Mechanically stable pharmaceutical presentations form containing liquid or semisolid surface-active substances

ABSTRACT

The present invention relates to mechanically stable pharmaceutical presentations for oral administration, comprising in addition to one or more active ingredients and at least one melt-processable matrix-forming excipient more than 10 and up to 40% by weight of a surface-active substance with an HLB of from 2 to 18, which is liquid at 20° C. or has a drop point in the range from 20 to 50° C.

BACKGROUND OF THE INVENTION

The present invention relates to mechanically stable pharmaceuticalpresentations for oral administration, comprising in addition to one ormore active ingredients and at least one melt-processable matrix-formingexcipient more than 10 and up to 40% by weight of a surface-activesubstance with an HLB of from 2 to 18, which is liquid at 20° C. or hasa drop point in the range from 20 to 50° C. A process for producing suchforms has also been found.

The production of pharmaceutical preparations by the melt extrusionprocess is known per se. Thus, the process described, for example, inEP-A 240 904 or EP-A 240 906 makes it possible, by a specific selectionand defined mixtures of the excipients employed, to control specificallythe properties of the formulations to be produced.

For example, it is possible to produce, by selecting suitable matrixpolymers, preparations which release the active ingredient continuouslyover a lengthy period. On the other hand, it may be desirable, forexample in the case of analgesics, for the active ingredient to dissolverapidly and be released quickly. The melt extrusion process has provento be suitable for producing rapid release and slow releaseformulations.

A basic requirement is, however, that the active ingredient is able todissolve sufficiently in the aqueous medium in the digestive tract.Absorption of the active ingredient is possible only if it is indissolved form, because only dissolved active ingredients can cross theintestinal wall. Active ingredients of low solubility may therefore notbe absorbed sufficiently and, associated with this, have a lowbioavailability.

There have been no lack of attempts to improve the bioavailability ofactive ingredients of low solubility (cf. R. Voigt; “PharmazeutischeTechnologie”, published by Ullstein Mosby, 7th edition, 1993, pages80-85). In particular, the production of coevaporates or so-called soliddispersions, in which the active ingredient is in the form of amolecular dispersion in an excipient matrix, has frequently provedadvantageous for increasing the bioavailability. When the drug formdissolves in the body, the active ingredient can be released inmolecular form from such solid dispersions directly and withoutsupplying energy of salvation.

However, the use of solid dispersions has a beneficial effect on thebioavailability of the active ingredient only if the active ingredientcan also undergo rapid absorption. However, if the absorption process isslow, the active ingredient of low solubility recrystallizes in theaqueous medium of the intestinal lumen because a supersaturated solutionof active ingredient may be produced on dissolution of the drug form.For this reason, the bioavailabilities which can be achieved even withsolid dispersions are often unsatisfactory.

The absorption of the active ingredient is often insufficient alsobecause the active ingredient is released too slowly from the tablet.Absorption of most active ingredients into the blood circulation takesplace in the upper sections of the small intestine, i.e. relatively soonafter passing through the stomach. Active ingredients which have notbeen adequately solubilized on reaching this region of the smallintestine can be absorbed to only a limited extent.

It is therefore crucial for achieving optimal absorption rates,especially of active ingredients of low solubility which readilycrystallize, to achieve rapid and sufficiently long-lastingsolubilization in the aqueous medium of the digestive tract withoutrecrystallization occurring.

The addition of surface-active substances is appropriate for this. Theaddition of surface-active substances to formulations of activeingredients of low solubility is generally known per se.

U.S. Pat. No. 5,834,472 discloses, for example, that the bioavailabilityof an antifungal agent can be improved by using a nonionicsurface-active substance.

However, since most surface-active substances are liquid or semisolid atroom temperature, the preparations produced to date are usually oilyliquids or semisolids used to fill hard or soft gelatin capsules.However, in the case of soft gelatin capsules, interactions betweenexcipients and the gelatin shell of the capsule are frequent and lead toleakage from the capsule.

The use of surface-active substances in tablet formulations is notpossible without problems either because the liquid or semisolidsurface-active substances impede compressibility in the conventionaltableting process, especially when larger amounts of surface-activesubstances in the region of more than 10% by weight are needed tosolubilize the active ingredient.

It is an object of the present invention to find mechanically stablesolid formulations for oral use which can be used in particular forrapid and nevertheless long-lasting solubilization of active ingredientsof low solubility after they have been liberated from the drug form.

BRIEF SUMMARY OF THE INVENTION

We have found that this object is achieved by the pharmaceuticalformulations defined at the outset, and a process for producing them.

DETAILED DESCRIPTION OF THE INVENTION

The active ingredients which can be used are in principle all human andveterinary pharmaceutical substances, and active ingredients used infood supplements.

Particularly suitable active ingredients are immunosuppressants,protease inhibitors, reverse transcriptase inhibitors, cytostatics orantimycotics, in addition to CNS-active substances or dihydropyrimidinederivatives.

It is possible in particular to formulate active ingredients of lowsolubility or low bioavailability according to the invention. Lowsolubility means that the solubility in an aqueous medium is less than 1mg/ml. Such active ingredients are also referred to in USP XXII, page 8,as scarcely soluble or practically insoluble.

Examples of active ingredients of low solubility are esuprone,nifedipine, ciclosporin or Taxol.

Suitable and preferred surface-active substances are low molecularweight substances which have an HLB (HLB—hydrophilic lipophilic balance)and are liquid at 20° C. or have a drop point in the range from 20° C.to 50° C., preferably up to 40° C. Preferred substances have an HLB offrom 7 to 18, particularly preferably 10 to 15.

Examples of suitable surface-active substances are saturated andunsaturated polyglycolized glycerides, semisynthetic glycerides, fattyacid esters or ethers of fatty alcohols as long as they have theproperties stated above.

The corresponding sorbitan fatty acid esters or ethoxylated sorbitanfatty acid esters are particularly suitable, such as, for example,polyoxyethylene 20 sorbitan monolaurate, polyoxyethylene 20 sorbitanmonopalmitate, polyoxyethylene 20 sorbitan monostearate, polyoxyethylene20 sorbitan monooleate, polyoxyethylene 20 sorbitan tristearate,polyoxyethylene 20 sorbitan trioleate, polyoxyethylene 4 sorbitanmonostearate, polyoxyethylene 4 sorbitan monolaurate or polyoxyethylene4 sorbitan monooleate. Also suitable are macrogol 6 cetylstearyl etheror macrogol 25 cetylstearyl ether.

Particular preference is given to polyoxyethylene glycerol ricinoleate35, polyoxyethylene glycerol trihydroxystearate 40, PEG 66012-hydroxystearate (polyglycol ester of 12-hydroxystearic acid (70 mol%)with 30 mol% ethylene glycol).

The surface-active substances are present in the preparations in amountsof more than 10% by weight based on the total weight of the preparation,and up to 40% by weight, preferably 15 to 25% by weight and particularlypreferably 20 to 25% by weight.

The preparations according to the invention also comprise at least onemelt-processable matrix excipient. Particularly suitable matrix-formingexcipients are water-soluble pharmaceutically acceptable polymers orsugar alcohols or mixtures thereof as long as they can be melted withoutdecomposition.

Pharmaceutically acceptable polymers are, in particular, homo- andcopolymers of N-vinylpyrrolidone such as polyvinylpyrrolidone withFikentscher K values of from 12 to 100, in particular K 17 to K 30, orcopolymers with vinyl carboxylates such as vinyl acetate or vinylpropionate, for example copovidone (VP/VAc-60/40).

Also suitable are polyvinyl alcohol or polyvinyl acetate, which may alsobe partially hydrolyzed, or acrylate polymers of the Eudragit type.

Also suitable are cellulose derivatives such as hydroxyalkylcelluloses,for example hydroxypropylcellulose, or, if slower release is required,hydroxyalkylalkylcelluloses which swell in water, for examplehydroxypropylmethylcellulose (HPMC), preferably with degrees of methoxysubstitution in the region of 22% and degrees of hydroxypropoxysubstitution in the region of 8%, particularly preferably HPMC typeswith viscosities of 4000 mPas, 15,000 mPas or 100,000 mPas, measured at20° C. in 2% by weight aqueous solution. Also suitable are HPMC typeswith degrees of methoxy substitution in the range from 28 to 29% anddegrees of hydroxypropoxy substitution in the range from 5 to 8.5%.

Likewise suitable are meltable sugar alcohols such as, for example,sorbitol, maltitol, isomalt, mannitol, xylitol, erythritol or mixturesthereof. Maltitol, mannitol, xylitol or isomalt is preferred.

Suitable matrix-forming polymers are also polyethylene glycols withmolecular weights in the range from 1000 to 20,000,000 Dalton,preferably 4000 to 10,000 Dalton.

The preparations may additionally contain conventional pharmaceuticalexcipients such as flavorings, antioxidants, silicas, release agents ordyes in the amounts usual therefor.

The preparations according to the invention are produced by a meltprocess. The process is preferably carried out without addition ofsolvents.

The melt process is carried out in a kneader or a screw extruder.Examples of suitable kneaders are those supplied by Haake or Farrell.

The melt is preferably produced in a screw extruder, particularlypreferably a twin screw extruder with and without kneading disks orsimilar mixing elements. Corotating twin screw extruders areparticularly preferred.

Depending on the composition, the processing generally takes place attemperatures from 40° C. to 260° C., preferably 50 to 200° C.

The starting materials can be fed into the extruder or kneader singly oras premix. They are preferably added in the form of powdered orgranulated premixes. Thus, the liquid or oily surface-active substancecan previously be mixed with another starting material to givefree-flowing granules. Addition of the surface-active substance inliquid form, for example by liquid pumps, which are preferably heated inthe case of semisolid substances, is likewise possible.

It is also possible first to dissolve the active substance in thesurface-active substance, and then to granulate this mixture with thepolymer. In this case, the active ingredient must not itself melt.

It may also be advisable for temperature-sensitive active ingredientsfirst to melt the other starting materials and only then to add theactive ingredient.

The starting materials are accordingly processed together to form amelt, which is processed by input of mechanical energy, in particular inthe form of shear forces, to a homogeneous composition.

The homogenous melt is then extruded through a die or a breaker plateand subjected to shaping. This can take place by pelletizing theextrudate by usual techniques, for example using rotating knives orcompressed air, to result in pellets or granules. The shaping can alsotake place as described in EP-A 240 906, by the extrudate being passedbetween two counter-rotating calender rolls and being shaped directly totablets. It is likewise possible to pass the melt through the openextruder head and, after solidification, further process whereappropriate by grinding or by suitable granulation equipment such asroll mills or compacting units.

Granules or pellets can then be processed to tablets in conventionaltablet presses. It is also possible for the preparations which have beeninitially obtained by calendering already in the form of mechanicallystable tablets to be subjected to a grinding process and then to becompressed to tablets in a conventional way. If required, the tabletscan then be provided with a conventional coating.

It is surprisingly possible according to the invention to obtain tabletswhich, despite a high proportion of liquid or semisolid surface-activesubstances, have good mechanical stability and are not prone to be tackyor to soften. The good dimensional stability of the preparations makesit unnecessary, according to the invention, to use them for fillingcapsules.

The resulting drug forms comprise the active ingredient embeddedamorphously. The preferred result is solid dispersions in which theactive ingredient is in the form of a molecular dispersion. The drugforms according to the invention make it possible for even activeingredients of low solubility to be sufficiently solubilized and stablydispersed in aqueous medium.

The preparations according to the invention form, after dissolving inaqueous medium, in particular at pH 1, for at least one hour a stablesolubilizate or a stable dispersion, in which the active ingredient ispreferably not in crystalline form.

EXAMPLE 1

50 g of a powdered mixture of 40% by weight of esuprone, 35% by weightof polyvinylpyrrolidone K 17 (PVP) and 25% by weight of polyoxyethyleneglycerol trihydroxystearate 40 as surface-active substance were producedby initially producing a powdered premix of esupron and the PVP, intowhich the surface-active substance was mixed at 20° C. until homogeneousgranules resulted.

EXAMPLE 2

The granules obtained in Example 1 were kneaded at a temperature of 100°C. in a heatable kneader (supplied by Haake) to a homogeneous melt.After cooling to 20° C., the melt was solid and was broken into smallfragments.

EXAMPLE 3

250 g of the granules obtained in Example 1 were stirred into 50 ml ofwater at room temperature. There was formation after a few minutes of acloudy suspension from which crystalline esuprone sedimented.

EXAMPLE 4

The melt granules obtained in Example 2 were stirred into water inanalogy to Example 3. After only a few minutes an opalescent solutionformed, and no esuprone had separated out of this even after one hour.

We claim:
 1. A mechanically stable pharmaceutical presentation for oraladministration, comprising one or more active ingredients, at least onemelt-processable matrix-forming excipient selected from the groupconsisting of homo- and copolymers of N-vinylpyrrolidone, acrylatepolymers and cellulose derivatives, and more than 10 and up to 40% byweight of a surface-active substance with an HLB of from 2 to 18, whichis liquid at 20° C. or has a drop point in the range from 20 to 50° C.,obtainable by mixing the starting materials in the melt without additionof solvents and subsequently shaping.
 2. A preparation as claimed inclaim 1, comprising from 15 to 25% by weight of surface-activesubstance.
 3. A preparation as claimed in claim 1, comprising asurface-active substance with an HLB of from 10 to
 15. 4. A preparationas claimed in claim 1, comprising a surface-active substance with a droppoint in the range from 20 to 40° C.
 5. A preparation as claimed inclaim 1, comprising macrogol glycerol hydroxystearate, polyoxyethylenericinoleate 35 or PEG 660 12-hydroxystearate as surface-activesubstance.
 6. A process for producing mechanically stable pharmaceuticalpresentations as claimed in claim 1 by a melt process, which comprisesprocessing one or more active ingredients, at least one melt-processablematrix-forming excipient and more than 10 and up to 40% by weight of asurface-active substance with an HLB of from 2 to 18, which is liquid at20° C. or has a drop point in the range from 20 to 50° C., in the meltto a homogeneous mixture, and shaping the latter to presentations.